Inhibition of Monoacylglycerol Lipase Reduces the Reinstatement of Methamphetamine-Seeking and Anxiety-Like Behaviors in Methamphetamine Self-Administered Rats

Abstract

BackgroundMethamphetamine is a highly addictive psychostimulant with reinforcing properties. Our laboratory previously found that Δ8-tetrahydrocannabinol, an exogenous cannabinoid, suppressed the reinstatement of methamphetamine-seeking behavior. The purpose of this study was to determine whether the elevation of endocannabinoids modulates the reinstatement of methamphetamine-seeking behavior and emotional changes in methamphetamine self-administered rats.MethodsRats were tested for the reinstatement of methamphetamine-seeking behavior following methamphetamine self-administration and extinction. The elevated plus-maze test was performed in methamphetamine self-administered rats during withdrawal. We investigated the effects of JZL184 and URB597, 2 inhibitors of endocannabinoid hydrolysis, on the reinstatement of methamphetamine-seeking and anxiety-like behaviors.ResultsJZL184 (32 and 40 mg/kg, i.p.), an inhibitor of monoacylglycerol lipase, significantly attenuated both the cue- and stress-induced reinstatement of methamphetamine-seeking behavior. Furthermore, URB597 (3.2 and 10 mg/kg, i.p.), an inhibitor of fatty acid amide hydrolase, attenuated only cue-induced reinstatement. AM251, a cannabinoid CB1 receptor antagonist, antagonized the attenuation of cue-induced reinstatement by JZL184 but not URB597. Neither JZL184 nor URB597 reinstated methamphetamine-seeking behavior when administered alone. In the elevated plus-maze test, rats that were in withdrawal from methamphetamine self-administration spent less time in the open arms. JZL184 ameliorated the decrease in time spent in the open arms.ConclusionWe showed that JZL184 reduced both the cue- and stress-induced reinstatement of methamphetamine-seeking and anxiety-like behaviors in rats that had self-administered methamphetamine. It was suggested that a decrease in 2-arachidonoylglycerol in the brain could drive the reinstatement of methamphetamine-seeking and anxiety-like behaviors.

Consideration of sex as a biological variable in the translation of pharmacotherapy for stress-associated drug seeking

“…This is in surprising contrast to the finding that CB1R antagonists also increase circulating ACTH and CORT ( Manzanares et al, 1999 ; Patel et al, 2004 ). To further complicate interpretation, chronic administration of the FAAH inhibitor URB597 during withdrawal suppressed pharmacological stressor-induced reinstatement of cocaine-seeking ( Chauvet et al, 2014 ), while acute URB597 administration did not ( Nawata et al, 2019 ). Nawata et al (2019) also report that systemic inhibition of monoacylglycerol lipase, the primary hydrolytic enzyme for 2-AG, using JZL184 reduced both anxiety and methamphetamine-seeking during footshock in a CB1R-dependent manner.…”

“…To further complicate interpretation, chronic administration of the FAAH inhibitor URB597 during withdrawal suppressed pharmacological stressor-induced reinstatement of cocaine-seeking ( Chauvet et al, 2014 ), while acute URB597 administration did not ( Nawata et al, 2019 ). Nawata et al (2019) also report that systemic inhibition of monoacylglycerol lipase, the primary hydrolytic enzyme for 2-AG, using JZL184 reduced both anxiety and methamphetamine-seeking during footshock in a CB1R-dependent manner. This seemingly contrasts with the findings by McReynolds et al (2018) , which showed that 2-AG synthesis in PrL-PFC was necessary for potentiated cocaine seeking following footshock.…”

URB597 abrogates anxiogenic and depressive behaviors in the methamphetamine-withdrawal mice: Role of the cannabinoid receptor type 1, cannabinoid receptor type 2, and transient receptor potential vanilloid 1 channels

“…Besides this, Δ 8 -tetrahydrocannabinol, an exogenous cannabinoid, suppresses the reinstatement of METH-seeking behavior. An inhibitor of MAGL, JZL184, can reduce the cue- and stress-induced reinstatement of METH-seeking and anxiety-like behaviors in METH self-administered rats (Nawata et al, 2019).…”

JZL184 increases anxiety-like behavior and does not reduce alcohol consumption in female rats after repeated mild traumatic brain injury.

“…Furthermore, it is known that low doses of CB1 receptor agonists produce anxiolytic-like effects whereas high doses produce anxiogenic-like effects 67,90 . It is possible that our dosing regimen mimicked the effects of a high dose of CB1 receptor agonists, but prior work showed anxiolytic-like effects of high JZL184 doses (32mg/kg and 40mg/kg i.p) during withdrawal from methamphetamine self-administration in rats 93 . Again, it must be remembered that we administered the drug days before anxiety-like behavior testing, which differs from most prior work.…”